DIEN DAN YHOC,
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GENE TRI LIEU CHO BENH NHAN LOC MANG BUNG:
CACH TIEP CAN MOI TRONG OIEU TRI
Do Gia Tuyen*, Dinh Thj Kim Dung''
Mpi trong nhirng lien bd rd ret nhdt Irong cdng nghe sinh hgc Irong vdng 25 ndm qua Id cdc ky thudt mdi ve gen, cdng nghe ndy bao gdm: qud Irinh nhdn dgng. phdn lap vd chuyen gene. Nhung ky ihudi mdi ve gen ndy cimg vcri nhung lien bp vugt bgc Irong giai md gen ciing ve sinh hgc vd lin hgc ma loung ednh cuu trong viic nhdn dgng hdng logt cdc gen lien quun den nhirng binh ly khde nhau. Dua Iren cdng nghi sinh hgc ndy. cdc nhd khou hgc dd cd the thiic ddy su hogt dpng cuu mpt sd gen cd tdc dung dieu chinh hodc duy fri sir hogt dpng ciiu cdc le hdo. Qud Irinh link ddy sir hogt dpng cua mpt gen don le hodc mpf logt cdc gen nhdm mpt muc dich cu the ndo dd Id mgi ky- thudt mdi cua cdng nghe sinh hgc md ngudi ta ggi Id gen Iri lieu fgene therapy). Ddy Id mat budc liin quan Irgng mang linh dpi phd Irong viic diiu tri mpt sd binh thdng qua su thuc ddy hogt dpng cua gen md chimg lu mang mudn, trong trirdng hgp ndy gen dd tgm dugc ggi do Id gen dich. Phirang phdp ndy ro rdng dd ldm thay ddi todn bp bp mgt ciiay hgc hien dgi irong Ihi ky 21. Muc lieu cua gen Iri lieu cho benh nhdn lgc mdng bung (LMB) di diiu fri suy than mgn buo gdm: duy Iri. buo ve su nguyen ven cuu le bdo cdu thdnh mdng bung hodc cdc le bdo n~ong khoang mdng bung, thiic ddy bao Idn cdu triic vd chirc ndng cua mdng bung, duy tri vd Idng kha ndng tgc cuu mdng bung.
L KHAI NIEM VE GEN TRI LIEU
Gen trj lieu la mgt phuong phap irng dung ebng nghe sinh hgc lien quan den mbt loat cae qua trinh sinh hge de dieu tri mgt benh hoac mgt trang thai benh ly man tinh thbng qua viec dua gen dich vao mbt loai te bao eiia ngubi benh va qua su hoat dgng (bieu hien) eiia gen nay se dan den sy thay dbi ve kieu hinh hoac the dich ma gen db quy djnh.
Gen trj lieu dugc de cap den la vao dau nhirng nam 80 ciia the ky trube de dieu tri mgt sd benh ly gay nen do su khiem khuyet ciia mgt gen don le.
Ci thdi diem do ngudi ta eho rang db la mgt birbe tien vugt bae va d\xac coi la mgt phuong phap ed the nhanh ehdng lam thay doi toan bb the gidi y hgc. Dimg gen tri lieu de thay the eae gen khong eb ehuc nang do benh ly hoac cae gen khbng hoat dbng hoac hoat dbng khbng hoan hao.
*Dgi hgc Y Hd Npi
**Khou Than-Tiet nieu. Benh viin Bgch Mai
Gen trj lieu lan dau tien dugc dua ra thii' nghiem vao thang 9/1990 de dieu trj mgt benh ly bam sinh rat hiem gap la benh thieu hut Adenosine deaminase. Sau hon 10 nam benh nhan dau tien dugc ap dung phuong phap gen tri lieu, phuong phap nay khong phai bao gib cung dat dugc nhu mong dgi ban dau, nb da nay sinh mbt sb van de lien quan den qua trinh van ehuyen gen dich vao trong te bao ciia co' the benh nhu: lam the nao de dat duge miie do bieu hien cua gen phii hgp nhu mong mubn? Vbi nhung khb khan nay cac nha khoa hgc da nhan ra rang qua trinh gay benh hoac mbt trang thai benh ly la mbt qua trinh phiie tap va dong bg xet ve khia canh sinh hgc ve gen. Cae nha khoa hgc da nhat tri rang: mbt benh, mbt tinh trang benh ly cb the duge gay nen hoae phbi hgp bbi nhieu gen khae nhau va phai can nhieu nghien
S6 49 (Thang 02 / 2010) Y HOC L A M S A N G | 7
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DIEN OAN YHOC
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eiru ca ban sau hon nira irudc khi gen trj lieu dugc dua vao irng dung rcing rai tren lam sang. Hon nira viec cip dung gen trj lieu can phai dugc quan ly rat chat che tren khia canh \a hgi. Chinh vi \a\ ma trao lirii dua gen lieu phap \ao thuc hanh lam sang da bj lang xuong phan nao. tu} nhien cac ngliien ciru ve gen trj lieu van tiep tue dua ra cac ket qua het sire kha quan.
Mgt so bao cao gan day \c dieu trj benh do thieu hut yeu to XI do ngii\en nhan mien djch o- tre em bang gen trj lieu da cho ket qua het sire kha quan. Cho den nay da ed hang nghin nghien ciru gen trj lieu ducjc tien hanh tren the gidi lien quan den hiing nghin benh nhan. trong do hau het la cac benh nhan mac cac benh ung thu. 1 u\ nhien. khong it thu nghiem lam sang da dirge ap dung tren benh nhan mac mgt so benh do don gen gay nen hoac mgt so benh man tinh. Trong dieu trj suy than man bang phuong phap lgc mang biing (LMB) gen trj lieu Cling da dugc cac nha khoa hoc dau tu nghien ciru va budc dau da cho ket qua dang khich le.
Gen lieu phap ap dimg CIK-I doi tugng Igc mang bung (LMB) bao gcim: qua trinh van clni_\en gen. tac dgng len cae qua trinh sinh hgc cua mang bung thong qua mgt loat cac yen to lien quan. \an chuyen gen vao te bao cau thanh cua mang bung va khoang mang bung...Trong bai viet nay chimg tbi xin gidi thieu ve khai quat \ e tac dgng cua gen trj lieu cho benh nhan suy than man dieu tri bang Igc mang bung.
II. GEN TRI LIED CHO BENH NHAN LOC MANG BUNG
Gen trj lieu dugc ap dung nhu the nao cho benh nhan LMB? Cimg giong nhu gen trj lieu ap dung cho bat ky mgt benh nao khac. dieu quan trgng can phai xac djnh can tac dgng vao qua trinh nao ha\ tac dgng vao mgt yen to cu the nao'!' Mgt dieu hien nhien la d benh nhan su\ than man Igc mang bung, mang bung se thay doi rat nhieu ca ve
cau tnic lan chirc nang theo thdi gian Igc. Nhirng sir thay doi bao gom: qua trinh da\ len cua lap te bao can thanh mang bung, sir lang dgng ciia cac chat nen ngoai bao va collagen, chinh nhimg qua trinh nay se lam giam kha nang dan hoi cua mang bung, hinh thanh nen cac mach man tan tao. qua trinh thoai hoa vi mach cua mang bung, tang sy liing dgng cua cac san pham chuyen hba....Nhiing thay doi nay dan den giam hieu qua cua qua trinh Igc tham chi dan den suy Igc cua mang hung va hau qua cuoi cimg la phai dimg lai phuong phap nay thay bang phuong phap dieu trj thay the khac nhu ghep than, than nhan tao...
Miic tieu cua gen trj lieu cho benh nhiin LMB:
duy tri. bao ve su nguyen ven eua te bao can thanh mang bung hoac cac te bao trong khoang mang biing. Qua trinh nay nham bao ton cau tnic va chirc nang ciia mang bung bao ton hoac lam tang kha nang Igc ciia mang biing. Vdi muc tieu nhu vay.
gen tri lieu ap dimg cho I,MB se nham ean thiep vao cac khau sau day: I. Ngan ngira qua trinh xo- hoa - mgt qiui trinh co the xa\ ra ddi vdi mang bung theo thai gian Igc. 2. Thiic day kha nang van chuyen hoac ngan ngira cac tac dgng co hai do cac goc ty do gay nen eho mang bung.
Trudc khi tien hanh gen trj lieu noi chung va cho Igc mang bung nbi rieng mgt sb cau hoi sau day can phai dugc tra ldi:
/. Tmh Irung benh ly hien Igi cua benh nhdn nhu the ndo? gen ndo se dugc chgn ldm gen dich'
2. Khu ndng gen tri lieu cd dieu chinh dugc khdng'.'' gen dich se thdng qua mpi yen id cu the ndo'.-' Gen dich ldc dpng Iren yeu id do Id gi'.' Kich thich huy hem che su hieu hien cuu gen quy dinh yen td do'.'
3. .\'hirng te bdo ndo se Id dich cho qud Irinh mang gen vd phuong lien vgn chuyin gen ndo Id phu hgp nhdt'.-'
4. Gen Iri lieu chi can don Iri lieu (mdi ldn
8 I Y H O C L A M S A N G 56 49 (Thang 02/201 Oj
DiEN D A N YHOC.
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ap dung nhiim tac dgng len mgt tinh trang cap tinh hoac man tinh.
Can cir vao qua trinh sinh ly cua mang himg trong qua trinh Igc va sy tham gia tac dcing cua cac yen td khac nhau mgt so gen sau co the dugc chgn lam gen dich trong khi chgn gen trj lieu, (bang I).
Bdng 1. Tmh trgng henh ly vd gen dieh ed the lira chgn duy nhdt) huy cdn phui ldp lgi nhieu tun'.'
5. Ldm the ndo de dieu hdu huy dieu chmh dugc mirc dp hieu hien hogt dpng cua gen dich'.'
Gen tri lieu cho Igc man"; bung cd the dugc
STT 1 2
4
Tinh trang benh ly Tinh trang viem
Bao tcin sir nguyen ven cua mang bimg:
- Tang cudng kha nang tieu sgi huyet - Tang cudng kha nang chong dong - Giam thieu tac hai cua goc tir do Tinh trang giam kha nang van chuyen ciia mang bung
Qua trinh xo- hoa mang bung
Gen dich IL-10:l-lRA;sTNFrp55:NFkB
tPA ; iiPA.PAI-l antisense thrombomodulin catalase
HAS; khang VEGF
Khang TGF-B (..decorin: HSP47 ire che lang dgng collagen)
Chil thich:
IL: interleukin: IL-1R.4: interleukin-1 receptor unlugonisi: sTNFrp55: soluble TNF receptor (55 KD):
NFkB.: nuclear factor kuppa B: I PA: tissue plusminogen aclivulor:
uP.4 :iirokinuse plusminogen activator: P.4I-I: plasminogen uclivulor inhibitor-l:
H.4S : hyliironan .synthase: VEGF : vascular endothelial gnnvlh factor:
TGF-fi : lran.sf'orming growth factor beta: HSP-C' :heal shock protein 47.
III. GEN TRI LIEU CAN THIEP VAO QUA TRINH VIEM MANG BUNG
Gen trj lieu co the lam thay doi qua trinh v iem mang bung cap - mgt tinh trang gay tbn thuong mang bung hoae lam thay doi qua trinh viem man tinh do mang bung tiep xiic vdi cac yeu to trong dich lgc.
Gen dich dimg trong gen tri lieu eo the tac dgng len cac te bao bieu mci cua mang bung hoac bach can. Mgt so gen co tac dimg khang viem co the lam giam qua trinh dap irng viem thong qua qua trinh ire che bach cau da nhan va cac dai thye bao va bao ve cac te bao ciia mang bung.
Mbt so gen cb the dugc chgn lam tien dich
bao gom: khang receptor eiia IL-1; yeu to chong hoai tir mo hoa tan va IL-10, yeu to ngan can sir hoat hda cua NFk beta- mgt yeu to thiic day qua trinh sao chep cua gen.
Qua trinh viem cd the dan den giai phong cac goc ty do va hau qua gay ton thuo-ng mang bung, mgt so gen cb tac dung chbng qua trinh oxy hda va khang goc tir do cd the dugc chgn lam gen dich trong gen trj lieu cho dbi tugng Igc miing bung.
IV. GEN TRj LIEU NHAM DUY TRI SU NGUYEN VEN CUA MANG BUNG
Mang bung se dan dan tro' len bj xo- hoa theo thai gian Igc hoac do tiic dgng cua qua trinh viem.
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Gen tri lieu co the dugc sir dung de duy tri sy nguyen ven cua mang bung, duy tri sir boat dgng sinh ly cua mang bimg.
Cac nha khoa hgc co the sir dung gen tPA de lam tang ty le tPA/PAI-1 hoac tang nbng do ciia urokinase-PA (uPA) hay ire che sy boat dgng eiia yeu to ire che PAI-1 trong viec ban che qua trinh tieu fibrin. De lam giam qua trinh hinh thanh va lang dgng fibrin d mang bung co the lam tang sy bieu hien ciia gen ma hba cho Thrombomodulin - mgt yeu to tham gia vao qua trinh chong dong.
Mat khac thong qua gen trj lieu bang each tang sy boat dgng ciia gen hyaluronan synthase se lam tang nong do hyaronan- mgt chat tham gia vao thiic day qua trinh lam lanh mang bung va lam tang kha nang trao dbi chat d mang bung (xem bang I).
V. GEN TRI LIEU NHAM HAN CHE QUA TRINH XO MANG BUNG
Thbng thuang mang bung se xo- hoa dan theo thai gian lgc doi vbi cac benh nhan lgc mang bung, nhanh hay chong la tiiy thugc vao tirng benh nhan cu the va trang thai benh ly cu the. Trong qua trinh gay XQ- mang bung TGF-B la mgt yeu tb dong vai trd quan trgng, khi nong do TGF-B tang len se dan den tang nhanh qua trinh xo- hda eiia mang bung.
TGF-B se bj tang miic do boat hda khi tiep xiic vbi mbi truang co nong do glucose eao va doi tirgng d trong tinh trang viem.
Khi TGF-B tang len a benh nhan Igc mang bung nd se thiic day mgt loat cac qua trinh sinh hge nhu: thiic day qua trinh tbng hgp yeu to tiing truang nbi bao, chat nen ngoai bao (ECM) va PAI-1.
Gen tri lieu dugc ap dung trong truong hgp nay nham muc dich: ngiin chan boat dgng cua TGF-B. De dat dugc muc tieu nay gen ma hda tbng hgp proteoglycans decorin - mgt yeu to ehbng tang sinh mach ed the duge sir dung lam gen dich.
Khi nong do ciia chat nay tang len se lam giam tinh trang tang sinh te bao ngi mo va ire che NFkB mgt yeu to tham gia vao khdi dgng qua trinh sao chep gen tong hop TGF-B va mgt loat cac cytokine tien viem khac.
VI.VAI TRO CUA TE BAO BIEU MO TRUNG MAC
Te bao bieu mo trung mac (BMTM) la te bao tham gia dau tien vao gen trj lieu cho benh nhan Ige mang bung. Nd cd tae dung mang gen dieh trong khoang mang bung. Do dae thii ve vj tri cho nen te bao nay tham gia vao rat nhieu cac hoat dgng sinh hgc dien ra trong khoang mang bung: qua trinh dap iing viem, tieu sgi huyet, qua trinh lam lanh vet thuong... Gen dieh tae dgng len nhirng qua trinh nay eb the huu hieu trong viec duy tri va thiie day boat dbng ciia mang bung a benh nhan suy than man dieu tri bang Ige mang bung.
Hon the nua te bao bieu mo trung mac khi bj kich thich se eb the tao ra mgt so yeu td, nd bai tiet trire tiep viio trong khoang mang bimg hoac vao cac mo cau thanh ciia mang bung ma nhQ-ng yen to nay se tham gia tryc tiep vao qua trinh thiic day sy boat dgng eiia te bao xung quanh va mbt so gen ngi sinh. Tuy nhien, te bao bieu md trung mac khbng phai la te bao duy nhat d khoang mang bung dbng vai trb la te bao dich eho gen tri lieu b benh nhan Igc mang bung. Mgt sb te bao khac cung ed the dugc sir dung nhu te bao dich trong gen tri lieu nhu: dai thuc bao, bach cau da nhan trung tinh, bach cau lympho, fbroblast va cac te bao nbi md.
Nhung te bao neu tren tham gia vao qua trinh bao ve miing bung, ehbng viem, chong xo- hba va tang qua trinh trao dbi chat cua mang bung. Tuy nhien, trong qua trinh ap dung chgn te bao nao lai phu thugc vao muc dieh ciia gen tri lieu eu the la gi khau nao can tae dbng...?
10 I Y HOC LAM SANG S6 49 (Thang 02 / 2010)
DiEN -DAN Y HOC,
;iiu#n <3e trong th^ng
VH. PHUONG TIEN MANG GEN VA DIEU HOA SU HOAT DONG CUA GEN
Phuong tien mang gen hay cdn ggi la vector cb the cb nguon gbe virus hoac khong phai la virus.
Virus mang gen a day thubng la: Adenovirus hay cb ngubn goc: Adenovirus. Retrovirrus. Herpes va Lentivirus. Phuong tien mang gen hay dimg trong gen tri lieu d Ige mang bung thuiTng la: Adenovirus tai to hgp.
Dilu hba sy boat dbng ciia gen dich dbng vai trd rat quan trgng trong gen trj lieu. Ve nguyen tae cb thg sir dung nhieu bien phap khac nhau de dieu chinh qua trinh boat dgng va bieu hien ciia gen tiiy theo each dua gen vao doi tugng. Sy bieu hien eb the chi la thoang qua (transient) hay lien tue va keo dai (permanent). Ngudi ta cd the dimg mgt sb thuoc de dieu chmh qua trinh nay.
TAI LIEU THAM KHAO
/. Catherine M. Hoff and Ty R. Shockley: Peritoneal Dialysis in the 21sl Century: The Polenliul of Gene Therupy .1 Am Soe Nephrol 13:Sin-SI24. 2002.
2. Culver KW: The first human gene therapy experiment.In: Gene Therapy: A Handbook for Physicians.
New York. Mary Ann Lieberl Inc.. 1994.pp 33-40.
3. Culver KW: Applications of gene therapy to non-neoplaslic disorders.In: Gene Therapy: A Handbook for Physicians. New York, Mary Ann Lieberl Inc., I994,pp 48-49.
4. Marshall E: Gene therapy on trial. Science 288: 951-957. 2000.
5. Cavazzanu-Culvo M. Hucein-Bev S. de Suini Busile G. Gross F. Yvon E. Nusbuum P. Selz F Hue C, Certuin S. Cusunovu .J-L. Boiisso P. LeDeisl F Fischer A: Gene therupv of humun severe immunodefi- ciency (SCID)-Xl disease. Science 288: 669-672. 200O
6. JoiirnulofGene Medicine. Gene therupy clinicul trials. Availuble al: hllp:/7www.wiley.co.uk/wileychi/
genmed/clinicul/. Accessed September 26. 2001.
7. Hoff CM, Shockley TR: Genetic modification of the peritoneal membrcme: Potential for improving peritoneal diulvsis through gene therapy. Semin Dial II: 218-227. 1998.
8. Hoff CM. Shockley TR: The polenliul of gene therupy in the periloneul cuvity. Peril Diul Inl 19 fSuppI 2J: S202-S207, 1999.
9. Dabble JW: Ultras true lure and pulholagy of the peritoneum in periloneul dialysis. In: Textbook of Peri- toneal Dialysis,edited by Gokal R, Nolph KD, Dordrecht. Kluwer 1994pp 17-44.
10. DiPaola N, Sacchi G: Alius ofperiioneal hislolog}- in normal conditions und during peritoneal diuly- .sis. Pent Dial Inl 20 fSiippl 3J: SI-S96 2000.
SUMMARY
THE POTENTIAL QF GENE THERAPY FOR PERITONEAL DIALYSIS
One of the greatest biofechnologic advunces of the last 25 year is genetic engineering - Ihe ubilily la identify und isolute individual genes und transfer genetic elements between cells. .4 gene therapy strategy bused on genetic modificution of the peritoneal membrane could improve the practice of
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;huy§n dfe trong thang
peritoneal diulvsis through the production of proteins that would be of iherapeutie value in preventing niemhrane damage and preserving its ilialvzing capacilv. The periloneul membrane can be geneticallv moilihed hv either ex vin, or in vivo gene transfer strategies with a vurielv of polentiallv therapeutic genes, including those for unli-inflummulorv cvlokines. fihriiiolvlic fuclors. und aniifibrotic molecules.
These genes could be administered either ou an acule basis, such as in response lo peritonitis, or on an intermittent basis to maintain phvsiologic homeostasis andperhups to prevent ihe adverse changes in the niemhrane that occur over time. The unlicipulecl effect of u gene iherupv slruleg\- could be measured in niuintenance of desired transport characlerislics and in patients being able lo remuin on the iherupv for longer periods of lime without the negative outcomes. In siimmurv. the use of a gene iherupv stralegv lo enhuuce peritoneal dialysis is an innovative and exciting concept with the potential lo provide new treatment plulforms for putients with end-stage renal diseuse.
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